Survival and clinical outcomes in patients with myelofibrosis and new or worsening anemia treated with ruxolitinib: A systematic review and meta-analysis

Abstract Introduction: Anemia is a common and clinically significant manifestation of myelofibrosis (MF). Both anemia and transfusion dependency are associated with inferior overall survival (OS). The JAK inhibitor ruxolitinib offers symptom relief, spleen volume reduction (SVR), and OS benefit, but it is often associated with worsening anemia. This meta-analysis evaluates the impact of new or worsening (n/w) anemia on OS and spleen response during ruxolitinib treatment, while capturing concurrent changes in ruxolitinib dosing. Methods: A systematic search of PubMed, Embase, and Cochrane databases (2010-April 2025) was conducted per PRISMA guidelines. Eligible studies included adult patients with MF treated with ruxolitinib (with or without anemia supportive care) and reported OS, event-free survival, transfusion dependence, hematologic outcomes, spleen outcomes, patient-reported outcomes, or ruxolitinib dosing or discontinuation among those with or without n/w anemia within the first 12 weeks of ruxolitinib treatment. Analyses were done using patient aggregated data. Patient-level data were reconstructed from published survival curves where needed. Bayesian meta-analysis was performed to obtain pooled estimates of the impact of n/w anemia on clinical outcomes, separately in baseline anemic and nonanemic patients. Base-case analyses included weakly informative priors for treatment effects and empirically informed priors for between-study variance. Results: Of 79 identified articles, 5 met the inclusion criteria, representing 3 distinct data sources: the phase 3b JUMP trial, the phase 3 COMFORT-I and COMFORT-II trials, and a real-world retrospective analysis using the US Flatiron electronic health record database. A post hoc analysis of ruxolitinib-treated patients in the phase 3 SIMPLIFY-1 trial was also included. The meta-analysis included 3028 eligible patients. Baseline anemia was defined as follows: hemoglobin (Hb) <10 g/dL in the JUMP and COMFORT studies; Hb <10 g/dL or an ICD-9/10 diagnostic code for anemia in the Flatiron analysis; and Hb <10 g/dL or being transfusion dependent in the SIMPLIFY-1 post hoc analysis. In the JUMP and COMFORT studies, n/w anemia was defined as an Hb decrease ≥1.5 g/dL from baseline or new transfusion requirement within 12 weeks of ruxolitinib initiation; in the Flatiron analysis and SIMPLIFY-1 post hoc analysis, n/w anemia was defined as an Hb decrease ≥1.5 g/dL from baseline and Hb <10 g/dL or new transfusion requirement within 12 weeks of ruxolitinib initiation. At baseline, 1231 patients were anemic (in 1138 evaluable, mean Hb = 8.8 g/dL), and 1797 were nonanemic (in 1682 evaluable, mean Hb = 12.3 g/dL). Mean age was 67.2 years, and 54.7% were male. Between the JUMP study and the SIMPLIFY-1 post hoc analysis, 62.4% had platelet counts ≥200×109/L. A total of 924 (51.4%) baseline nonanemic patients and 594 (48.3%) baseline anemic patients developed n/w anemia within 12 weeks of ruxolitinib initiation. Among baseline nonanemic patients, those who developed n/w anemia had 1.57 times the risk of death during follow-up vs those who did not (hazard ratio [HR], 1.57; 95% credible interval [CrI], 1.01-2.33). Patients with anemia (at baseline or n/w anemia during treatment) had more than twice the risk of death during follow-up vs those without (at baseline and n/w anemia during treatment) (HR, 2.26; 95% CrI, 1.60-3.07). No clear association was observed between the presence or absence of n/w anemia and achieving SVR ≥35% at week 24. In both baseline anemic and nonanemic subgroups, patients who developed n/w anemia had greater mean reductions in ruxolitinib dose (≈2 mg/day) during the first 12 weeks after initiation vs those without n/w anemia. Conclusions: N/w anemia within the first 12 weeks of ruxolitinib treatment was associated with increased mortality risk and numerically greater reduction in ruxolitinib daily dosing. Despite small ruxolitinib dose reductions and no clear difference in spleen outcomes, patients with anemia (at baseline or n/w anemia during treatment) had worse OS. These findings suggest that n/w anemia in MF during ruxolitinib treatment may have a detrimental impact on OS and highlight the importance of preventing and treating anemia progression in patients with MF. Follow-up beyond 12 weeks of treatment in future studies may provide additional insight on the impact of n/w anemia on clinical outcomes and whether improving anemia with alternative treatments improves survival.